It is increasingly recognised that individual risk of cancer may be related to genetically
determined differences in the ability of cells to identify and repair DNA damage. Cell
cycle based assays of chromosomal radiosensitivity provide the greatest power for
discriminating differences in response to DNA damage and it has been suggested that
individuals who are genetically susceptible to cancer show increased chromosomal
radiosensitivity. The relationship between chromosomal radiosensitivity and early onset
cancer was investigated in a population of Danish survivors of childhood and adolescent
cancer and a control group comprising of their partners using the G₂ assay of chromosomal
radiosensitivity. Heritability was also examined in the offspring.
No significant differences in radiosensitivity profiles were found between partner controls
and either the cancer survivors or offspring. However, when compared to the Westlakes
Research Institute control population, significant differences were observed with the
cancer survivors (P = 0.002) and offspring (P < 0.001), supporting an association of
chromosomal radiosensitivity with cancer predisposition. Heritability studies suggested
the majority of phenotypic variance of chromosomal radiosensitivity was attributable to a
putative major gene locus with dominant effect.
Since G2 chromosomal radiosensitivity indirectly measures the ability of cells to repair
DNA damage induced by ionising radiation exposure, variants in DNA repair genes may
explain inter-individual variation observed. Sixteen polymorphisms in nine genes from
four DNA repair pathways were investigated. Genotype frequencies at the Asp148Glu
polymorphism were associated with childhood cancer in survivors. Analysis of variance and FBAT analysis suggested significant associations at both the Thr241Met and
Ser326Cys polymorphism sites with G₂ radiosensitivity, but neither remained significant
after multiple-test adjustment.
This study invites further exploration of the predictive capacity of G₂ chromosomal
radiosensitivity in cancer predisposition. Clearly, further work is needed to correlate
radiosensitivity with genetic polymorphisms, which may underlie cancer susceptibility and
variation in radiosensitivity